The present invention relates to the art of administering bio-affecting agents to bio-systems, and, in particular, for rendering agents, which are substantially non-dissoluble in an aqueous environment, available for interaction with a host bio-system, e.g., a human or animal.
Bio-systems, such as humans, plants, insects, fish, birds, and mammals, are primarily aqueous systems. In order to effectively administer an bio-affecting agent to such bio-systems, it is necessary to make the agent available for interaction with physiological activity in the bio-system. This is referred to herein as xe2x80x9cbio-availability.xe2x80x9d In the case of bio-affecting agents which are non-dissoluble in an aqueous environment, as well as in the case of those which are only poorly water-soluble, effective administration of the bio-affecting agent can be difficult due to inadequate bio-availability of the agent and consequent low pharmacological activity. These solubility problems affect many parameters of administration, such as the method of administration, the rate of administration, the concentration of administration, etc.
It is known that rate of dissolution of drug particulates can be increased by increasing the surface area of the solid, i.e., decreasing the particle size. Consequently, methods of making finely divided drugs have been studied and efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. For example, dry milling techniques have been used to reduce particle size and thereby influence drug absorption. However, in conventional dry milling, as discussed by Lachman et al., The Theory and Practice of Industrial Pharmacy, Chapter 2, xe2x80x9cMillingxe2x80x9d, p. 45 (1986), the limit of fineness is reached in the region of about 100 xcexcm (=100,000 nm), where the milled material begins to cake onto the surfaces of the milling chamber. Lachman et al. note that wet grinding is beneficial in further reducing particle size, but that flocculation restricts the lower particle size limit to approximately 10 xcexcm (=10,000 nm). There tends to be a bias in the pharmaceutical art against wet milling due to concerns associated with contamination. Commercial airjet milling techniques have provided particles ranging in average particle size from as low as about 1 xcexcm to 50 xcexcm (=1,000 nm to 50,000 nm).
Other techniques for preparing pharmaceutical compositions with enhanced aqueous solubility properties include loading drugs into liposomes or polymers, e.g., during emulsion polymerization. However, such techniques have problems and limitations. For example, a lipid-soluble drug is often required in preparing suitable liposomes. Further, unacceptably large amounts of the liposome or polymer are often required to prepare unit drug doses. Further still, techniques for preparing such pharmaceutical compositions tend to be complex. A principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomer or initiator (which can be toxic) at the end of the manufacturing process.
U.S. Pat. No. 4,540,602 (Motoyama et al.) discloses a solid drug pulverized in an aqueous solution of a water-soluble high molecular weight substance using a wet grinding machine. However, Motoyama et al. teach that, as a result of such wet grinding, the drug is formed into finely divided particles ranging from 0.5 xcexcm (500 nm) to less than 5 xcexcm (5,000 nm) in diameter.
EPO 275,796 describes the production of colloidally dispersible systems comprising a substance in the form of spherical particles smaller than 500 nm. However, the method involves a precipitation effected by mixing a solution of the substance and a miscible non-solvent for the substance, and results in the formation of non-crystalline nanoparticles. Furthermore, precipitation techniques for preparing particles tend to provide particles contaminated with solvents. Such solvents are often toxic and can be very difficult, if not impossible, to adequately remove to pharmaceutically acceptable levels. Accordingly precipitation methods are usually impractical.
U.S. Pat. No. 4,107,288 describes particles in the size range from 10 to 1,000 nm containing a biologically or pharmacodynamically active material. However, the particles comprise a crosslinked matrix of macromolecules having the active material supported on or incorporated into the matrix.
U.S. Pat. No. 5,145,684 describes a method for providing drug particles having an effective average particle size of less than about 400 nm. The method includes wet milling the drug in the presence of a grinding medium in conjunction with a surface modifier. As in previous methods, the ""684 protocol requires grinding or milling to produce size reduction. The method further requires the use of an additive in the form of a surface modifier.
Moreover, drugs prepared by milling, even wet milling such as that described in the ""684 disclosure, are subject to degradation resulting from heat as well as physical and chemical trauma associated with fracture. Grinding also creates xe2x80x9chot spots,xe2x80x9d i.e., volumes of localized higher temperatures which can exceed the melting point or degradation of the drug. The process is also lengthy, requiring attrition exposure over several days. This type of process effectively exposes the drug to a long xe2x80x9cheat historyxe2x80x9d, wherein exposure to elevated temperatures has been significant, and the purity and potency of the drug is diminished to a significant extent. Furthermore, particles reduced by milling are often contaminated by the residue of the grinding operations, especially when ball milling is used and the grinding balls are worn down by abrasion.
It has also been known in the art of drug delivery to improve bio-availability by aggregating substantially non-dissoluble active ingredients on the surface of soluble substrates, such as water-soluble beads. The active ingredient can be deposited on such substrates by spraying a solution of the active ingredient over a fluidized bed while xe2x80x9cflashing offxe2x80x9d the solvent used for the active ingredient. This method is highly inefficient in that it requires several hours to deposit a sufficient amount of active ingredient to prepare a useable delivery system. Furthermore, an additional ingredient which is unnecessary to the system must be used, i.e., the solvent required to dissolve the active ingredient. As previously mentioned, the solvent must be flashed off during aggregation. Thus, this system is a long and cumbersome process and does not provide efficiency of dosage delivery.
Solubilization techniques for drugs which have low aqueous solubility require the use of organic solvents for processing in a solution state. This requires the use of expensive recovery systems for solvent handling capability. When general melt processing techniques are used to form dispersions, bulk melting and mixing steps often expose the drug to a prolonged heat history.
It is desirable to provide stable dispersible drug particles in the sub-micrometer size range which can be readily prepared in the absence of size reduction by grinding or milling. Moreover, it would be highly desirable to provide pharmaceutical compositions having enhanced bio-availability.
It is, therefore, an object of the present invention to overcome the disadvantages associated with methods for preparing delivery systems for bio-affecting ingredients, especially those which are substantially non-dissoluble. As a consequence of overcoming the drawbacks known in the art, it has been found that other and further objects which enhance the art of delivery systems have been realized as a result of the present invention.
The invention is a composition for delivery of a bio-affecting agent to a bio-system, and a methods of making and using a delivery system which includes a bio-affecting agent. The composition and method include the use of:
a solid dispersion of the bio-affecting agent in an increased-energy state in a water-soluble (or water-dispersible) polymer which is compatible with the agent and which has a glass transition temperature (Tg) in the range of from about 0xc2x0 C. to about 200xc2x0 C., whereby the agent is rendered bio-available in an aqueous environment.
Preferably, the water-soluble polymer is any polymer which has a glass transition temperature in the range of from about 25xc2x0 C. to about 150xc2x0 C., and more preferably in the range of from about 40xc2x0 C. to about 100xc2x0 C.
Preferred water-soluble polymers include poly(meth)acrylic acid polymers,containing acrylic and/or methacrylic moities. Preferably, the polymethacrylic acid polymers have the structure: 
wherein: R1, R2, R3, R4 are any substituents provided that the polymer has a glass transition temperature in desired range. Accordingly, R1, R2, R3, R4 preferably are independently hydrogen (H) or any alkyl, aryl, alkaryl, aralkyl, aminoalkyl, alkyl-substituted aminoalkyl, ammonioalkyl, or alkyl-substituted ammonioalkyl group. Still more preferably, R1, R2, R3, R4 in Structure (1) are independently H, C1-C6 alkyl, aminoalkyl, methyl- or dimethyl-aminoalkyl, or methyl-, dimethyl-, or trimethyl-ammonioalkyl. Yet more preferably, in Structure (1):
R1 is H, CH3;
R2 is H, CH3, C2H5, CH2CH2N(CH3)2;
R3 is H, CH3; and
R4 is CH3, C2H5, C3H7, C4H9, CH2CH2N(CH3)3+Xxe2x88x92, wherein Xxe2x88x92 is any monovalent anion.
A highly preferred water-soluble polymer is a terpolymer of butyl (meth)acrylate, (2-dimethyl aminoethyl) (meth)acrylate, and methyl (meth)acrylate in relative proportions 1:2:1.
Preferably, the water-soluble polymer is a polymer having pH-sensitive solubility in aqueous media. The water-soluble polymers preferentially have solubility in aqueous media having a pH of from about 1 to about 11. More preferably, the water-soluble polymer has solubility in acidic aqueous media, i.e., having a pH of about 7 or less.
The bio-affecting agent can be any agent known to have an effect in a biological system. Preferably, the bio-affecting agent is substantially non-dissoluble in an aqueous environment. More preferably, the bio-affecting agent has a solubility which is defined as practically insoluble or insoluble according to the USP. The bio-affecting agent is preferably selected from the group consisting of antifungals, anti-inflammatories, anti-hypertensives, antimicrobials, steroidal drugs, hormones, prostaglandins, interferons, and mixtures thereof.
Moreover, the composition comprising the bio-affecting agent and the water-soluble polymer preferably meets or exceeds USP dissolution standards for the agent.
The composition of this embodiment can include a solid dispersion provided by flash-flow processing a feedstock including the bio-affecting agent and the polymer. The flash-flow processing can be flash heat processing or flash shear processing. The flash heat processing method is particularly preferred when processing bio-affecting agents which are heat-sensitive. Alternatively, the solid dispersion can be provided by extrusion mixing for a time sufficient to form the solid dispersion. Preferably, the time of extrusion mixing is less than about 2 minutes, more preferably, less than about 30 seconds. When the solid dispersion is provided by extrusion mixing, it is highly preferred that the bio-affecting agent is an antifungal, anti-inflammatory, or anti-hypertensive agent.
The composition of the invention includes the bio-affecting agent in an at least substantially uniform or amorphous solid dispersion. Preferably, the bio-affecting agent is present in the form of nanoparticles distributed throughout the solid dispersion. More preferably, the nanoparticles have an average particle size of less than about 1,000 nm. Still more preferably, the average particle size of the nanoparticles is less than about 400 nm. The bio-affecting agent can be dispersed in the water-soluble polymer at the molecular level.
The composition can be prepared as a controlled-release particulate by mechanically reducing the solid dispersion. Preferably, the particulate is part of a dosage unit, which is preferably selected from the group consisting of capsules, tablets, and rapid-dissolve tablets. Alternatively, the solid dispersion is sized and shaped for fixation in an intravascular (or other parenteral) delivery apparatus. Moreover, the solid dispersion can be provided in the form of a slow dissolving structures such as a suppository or a lozenge or the like.
The method includes simultaneously transforming the bio-affecting agent to an increased-energy state and fixing the agent in that state. The method can include simultaneously transforming and fixing by flash-flow processing. This method includes use of flash heat processing or flash shear processing. Heat-sensitive agents are beneficially processed by flash heat processing. Alternatively, the simultaneous transforming and fixing can be effected by extrusion mixing for a time sufficient to form the solid dispersion, preferably for a time of less than about 2 minutes, more preferably less than about 30 seconds. In the latter approach, the bio-affecting agent is most preferably an antifungal, anti-inflammatory, or anti-hypertensive agent.
The method of transforming the bio-affecting agent into the increased-energy state can include reducing, in the absence of mechanical attrition, the bio-affecting agent to dispersed nanoparticles having an average particle size of less than about 1,000 nm. More preferably, the mechanical reducing yields an average particle size of the nanoparticles of less than about 400 nm. Alternatively, the method can be used to disperse the bio-affecting agent at a molecular level to provide a solid solution.
The method can further include mechanically reducing the solid dispersion to particulates. Thus, the method can further include incorporating the particulates in a dosage unit, such as a capsule or a rapid-dissolve tablet. Alternatively, the method can further include sizing and shaping the solid dispersion for fixation in an intravenous (or other parenteral) fluid delivery device. Lozenges, suppositories, and other slow release delivery structures can also be employed to deliver the bio-affecting agent.
The invention further includes method and composition for delivery of a bio-affecting agent. The composition produced by the method includes:
a) a carrier comprising a water-soluble polymer having a glass transition temperature in the range of from about 0xc2x0 C. to about 200xc2x0 C.; and
b) a bio-affecting agent microscopically dispersed in said water-soluble polymer.
Preferably, the water-soluble polymer has pH-sensitive solubility in aqueous media. In particular, it is preferred that the water-soluble polymer be substantially indissoluble in saliva but soluble in gastric fluid.
The invention is also a method for delivering a composition of a bio-affecting agent, as described, to a bio-system. The method includes
administering to the bio-system a solid dispersion comprising the bio-affecting agent fixed in an increased-energy state in a water-soluble polymer having a glass transition temperature in the range of from about 0xc2x0 C. to about 200xc2x0 C., wherein the solid dispersion renders the bio-affecting agent bio-available to the bio-system.
The method and composition of the invention possess numerous advantages over the prior art. For example, the method of processing a bio-affecting agent with a water-soluble polymer to form a solid dispersion according to the invention avoids use of solvents or mechanical attrition or comminution, which methods have various disadvantages detailed hereinabove. Moreover, the method substantially decreases the heat history of the bio-affecting agent, with the advantage that the agent remains substantially less degraded or decomposed throughout the processing. The method and composition of the invention also dramatically enhance the bio-availability of bio-affecting agents which are otherwise substantially non-dissoluble in aqueous environments, thereby enabling delivery of such agents to bio-systems with greater ease and simplicity and through more routes than has heretofore been possible.
These and further advantages will be appreciated by those skilled in the art in view of the following detailed description of the invention and the drawings as set forth below, and the scope of the invention will be pointed out in the appended claims.